Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of two chemotherapy regimens for recurrent and inoperable squamous cell carcinoma of the head and neck is reported. All patients had failed prior surgery and/or radiotherapy. 23 patients (group A) were treated with Cisplatin 120 mg/m2 and Adriamycin 60 mg/m2. 21/23 were evaluable for tumour response. The overall response rate (RR) was 28.5% (6/21, 2 CR and 4 PR). Methotrexate 250 mg/m2 with Leucovorin-Rescue 5 X 10 mg/m2 and 5-Fluorouracil 600 mg/m2 were administered to 28 patients. In 26 evaluable patients a RR of 38.4% (10/26, 5 CR and 5 PR) was achieved. The responders in groups A and B had a median survival of 98 and 85.5 weeks respectively and the non-responders 27 weeks in both groups. Nausea, vomiting and alopecia were common and severe in the DDP/ADM group. The major toxic effect of MTX/5-FU was neutropenia with two associated deaths from septicemia, although subjective side-effects were almost completely absent. MTX/5-FU can be recommended for the palliative treatment of recurrent squamous head and neck cancer because of an acceptable response rate, good subjective tolerance and the possibility of outpatient treatment.
HNO 1986 Jun
PMID:[Chemotherapy of recurrent squamous cell carcinomas in the ENT area with cisplatin/adriamycin (DDP/ADM) and methotrexate/5-fluorouracil (MTX/5-Flu): a retrospective comparison of 2 protocols]. 374 8

AIDS dementia complex (ADC) is a complex, progressive neuropsychiatric syndrome seen in 60-70% of the patients with AIDS. The structural and functional changes associated with ADC may be the result of a variety of indirect mechanisms mediated via activated brain cells or/and virus that produce neurotoxins including N-methyl-D-aspartate receptor agonist (eg, quinolinic acid, glutamate), cytokines, gp 120 and nitric oxide. The level of the neurotoxin and kynurenine pathway metabolite, quinolinic acid, is increased in the brain and CSF of HIV-1-infected patients, and is correlated with quantitative measures of neurologic impairment. Importantly, increased CSF and brain levels of QUIN also occur in other inflammatory neurologic diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicemia), independent of HIV-1 infection. Therefore, QUIN and other neuroactive kynurenine pathway metabolites may be final common mediators of neurologic dysfunction in a broad spectrum of inflammatory neurologic diseases. Conversion of L-tryptophan to QUIN has also been demonstrated in vitro in both brain tissue following macrophage infiltration, and in macrophages stimulated by interferon-gamma or HIV infection. Macrophages in vitro have a high capacity to synthesize QUIN following exposure to interferon-gamma, tumor necrosis factor-alpha, IL-1 beta and IL-6, compared to cells derived from other tissues. Notably, the concentrations achieved in the macrophage incubates exceeded the levels found in the CNS of HIV-1-infected patients, and exceeded the concentrations shown to be neurotoxic in vitro. We hypothesize that increased kynurenine pathway metabolism following inflammation reflects the presence of macrophages and other reactive cell populations at the site of brain infection. Strategies to attenuate the neurotoxic effects of kynurenines, such as inhibitors of kynurenine pathway metabolism and cytokine antibodies may offer new approaches to therapy.
 ...
PMID:[Biochemical studies on AIDS dementia complex--possible contribution of quinolinic acid during brain damage]. 747 52

Although the incidence of Gram-positive sepsis has risen strongly, it is unclear how Gram-positive organisms (without endotoxin) initiate septic shock. We investigated whether two cell wall components from Staphylococcus aureus, peptidoglycan (PepG) and lipoteichoic acid (LTA), can induce the inflammatory response and multiple organ dysfunction syndrome (MODS) associated with septic shock caused by Gram-positive organisms. In cultured macrophages, LTA (10 micrograms/ml), but not PepG (100 micrograms/ml), induces the release of nitric oxide measured as nitrite. PepG, however, caused a 4-fold increase in the production of nitrite elicited by LTA. Furthermore, PepG antibodies inhibited the release of nitrite elicited by killed S. aureus. Administration of both PepG (10 mg/kg; i.v.) and LTA (3 mg/kg; i.v.) in anesthetized rats resulted in the release of tumor necrosis factor alpha and interferon gamma and MODS, as indicated by a decrease in arterial oxygen pressure (lung) and an increase in plasma concentrations of bilirubin and alanine aminotransferase (liver), creatinine and urea (kidney), lipase (pancreas), and creatine kinase (heart or skeletal muscle). There was also the expression of inducible nitric oxide synthase in these organs, circulatory failure, and 50% mortality. These effects were not observed after administration of PepG or LTA alone. Even a high dose of LTA (10 mg/kg) causes only circulatory failure but no MODS. Thus, our results demonstrate that the two bacterial wall components, PepG and LTA, work together to cause systemic inflammation and multiple systems failure associated with Gram-positive organisms.
 ...
PMID:The cell wall components peptidoglycan and lipoteichoic acid from Staphylococcus aureus act in synergy to cause shock and multiple organ failure. 747 84

Administration of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (5 mg/kg s.c.) provoked acute microvascular injury (assessed by the leakage of radiolabelled human serum albumin) in the rat colon within 1 h, when administered concurrently with endotoxin (Escherichia coli lipopolysaccharide, 3 mg/kg i.v.). Pretreatment with the selective inhibitor of 5-lipoxygenase, BW A137C (N-[4-benzyloxybenzyl] acetohydroxamic acid; 1-20 mg/kg s.c., 15 min before endotoxin) attenuated such damage in a dose-dependent manner. These findings suggest a balance between protective constitutive nitric oxide and the detrimental actions of 5-lipoxygenase products in the maintenance of vascular integrity in the early stage of sepsis.
 ...
PMID:Colonic microvascular integrity in acute endotoxaemia: interactions between constitutive nitric oxide and 5-lipoxygenase products. 749 98

The objective of this study was to determine whether endothelium-derived nitric oxide (NO) production is reduced at the macrocirculatory and microcirculatory levels during sepsis. To examine this, rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h after CLP (i.e., midpoint of hyperdynamic sepsis) or sham operation, the aorta and superior mesenteric artery were isolated. Responses to an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, nitroglycerin (NTG), were determined. In additional studies, the small intestine was isolated 5 or 20 h (hypodynamic sepsis) after CLP. Responses to ACh and NTG were determined in the isolated intestine. The results indicate that endothelium-dependent relaxation in both the aorta and superior mesenteric artery was depressed at 5 h after CLP. In contrast, there was no significant difference in the relaxation induced by NTG. Moreover, ACh-induced vascular relaxation in the isolated small intestine decreased at 5 and 20 h post-CLP without any significant alterations in NTG-induced relaxation. Since studies have shown that ACh-induced relaxation in the aorta is reduced at 20 h after CLP, it could be concluded that endothelium-derived NO release is depressed during hyperdynamic and hypodynamic stages of sepsis, not only in large arteries, but also at the microcirculatory level.
 ...
PMID:Endothelium-dependent relaxation is depressed at the macro- and microcirculatory levels during sepsis. 750 27

Septic shock is the host's inflammatory response to infection. There are multiple endogenous mediators responsible for the pathogenesis of septic shock. Cytokines, nitric oxide and prostaglandins are some of the major mediators. The term sepsis syndrome allows for an earlier diagnosis and treatment. Management of septic shock is focused in maintaining hemodynamic stability and an adequate oxygen delivery and utilization. Careful attention to each organ-system is of paramount importance to prevent complications and improve outcome. Experimental therapies to modulate the inflammatory response are promising.
 ...
PMID:Septic shock: pathogenesis and treatment. 750 55

Various cell types, including endothelial cells, can synthesize nitric oxide (NO). Three different isoforms of NO synthase have been characterized, purified and cloned. Isozyme I is present in neuronal cells of the brain (where NO may mediate synaptic plasticity), in peripheral non-adrenergic non-cholinergic (NANC) neurons (where NO acts as an atypical neurotransmitter relaxing vascular and non-vascular smooth muscle), and in various specialized epithelial cells. Macrophages can be induced with bacterial endotoxin and/or cytokines to express isozyme II. The high concentrations of NO produced by this isoform have cytostatic effects on parasitic microorganisms and tumour cells. A similar isozyme can be induced in the vascular wall (presumably in smooth muscle cells) in sepsis and during cytokine therapy. The large amounts of NO produced by this enzyme contribute to the symptoms of septic shock, such as vasodilatation and microvascular endothelial damage. Endothelial cells contain isoform III of NO synthase which seems to be unique for this cell type. Endothelium-derived NO is a physiologically significant vasodilator and inhibitor of platelet aggregation and adhesion. In addition, vascular NO can prevent leukocyte adhesion to the endothelium by interfering with the adhesion molecule CD11/CD18, and NO has also been shown to inhibit the proliferation of vascular smooth muscle cells. Hence, NO represents a protective factor against vascular damage and probably atherogenesis.
 ...
PMID:Isoforms of nitric oxide synthase: functions in the cardiovascular system. 750 35

Nitric oxide (NO) has been proposed as a mediator of hypotension in septic shock. The aim of this study was to determine whether an inhibitor of NO production, NG-monomethyl-L-arginine (L-NMMA), was able to protect against death in two murine models of experimental gram-negative sepsis. L-NMMA (3-300 mg kg-1) did not improve survival in intravenous or intraperitoneal models of sepsis. Seven h after intravenous infection, L-NMMA (100 mg/kg-1) reduced serum nitrite plus nitrate levels (NO breakdown products) from 774 microM in control-treated animals to 282 microM in L-NMMA-treated animals (P < .001). This compared to a level of 103 microM in uninfected mice. L-NMMA produced little change in bacterial load following infection and did not increase hepatic damage, as measured by serum levels of ornithine carbamoyltransferase. Thus, while L-NMMA may reverse the hyporesponsiveness of peripheral circulation in sepsis, it was unable to prevent death in these models of gram-negative septic shock.
 ...
PMID:Inhibition of nitric oxide synthase in experimental gram-negative sepsis. 750 68

Cytokine-inducible nitric oxide (NO) production has been implicated in the pathogenesis of septic shock. The present study was designed to determine which cytokines induce expression of the NO synthase gene in rat aortic vascular smooth muscle cells (VSMC) in vitro and whether NO synthase gene expression is inducible in vivo. NO synthase mRNA appeared after 4-h exposure to interleukin-1 beta (IL-1 beta), and levels continued to increase up to 24 h. Levels of NO synthase transcripts were greatest in VSMC treated with IL-1 beta (1 nM), lower in VSMC treated with Escherichia coli lipopolysaccharide (LPS; 100 micrograms/ml), and just detectable in VSMC treated with tumor necrosis factor-alpha (TNF-alpha; 1 nM). IL-1 beta, TNF-alpha, and LPS each induced NO synthase activity, assessed by release of nitrite, conversion of L-arginine to L-citrulline, and increased levels of guanosine 3',5'-cyclic monophosphate, whereas IL-2, IL-6, and interferon-gamma were ineffective. IL-1 beta was more potent and effective than TNF-alpha; however, submaximal concentrations of TNF-alpha acted synergistically with IL-1 beta to induce NO synthase gene expression and activity. Inducible NO synthase mRNA was present in aorta from rats 6 h after treatment with LPS (5 mg/kg), but not at 24 h. Synergistic activation of NO synthase gene expression in VSMC by IL-1 beta and TNF-alpha may contribute to hypotension in sepsis.
 ...
PMID:Interleukin-1 beta and tumor necrosis factor-alpha synergistically induce NO synthase in rat vascular smooth muscle cells. 751 63

Nitric oxide (NO) is an important hemodynamic mediator of sepsis; however, its visceral microcirculatory effects are largely unknown. To determine the role of systemic nitric oxide synthase (NO-S) inhibition on the microcirculation of the small intestine (SI), an intact loop of SI was exteriorized from decerebrate rats into a controlled tissue bath. Videomicroscopy was used to measure arteriolar diameters (A1, A3) and optical Doppler velocimetry was used to quantitate flow. In nonbacteremic controls inhibition of NO-S by N omega-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg IV) caused vasoconstriction (A1 = -7%; A3 = -24% baseline values) and reduced A1 flow by 26%. Bacteremic controls received 10(9) Escherichia coli IV, which resulted in arteriolar constriction and hypoperfusion (A1 = -16%; A3 = -21%; A1 flow = -44%), despite increased cardiac output (+33%). Treatment of bacteremic rats with L-NAME corrected the increased cardiac output (-3%), but exacerbated vasoconstriction (A1 = -24%; A3 = -27%) and did not improve A1 flow (-49%). These data indicate that (1) NO mediates basal microvascular tone of the SI; (2) hyperdynamic bacteremia causes arteriolar constriction and hypoperfusion of the SI; and (3) although systemic NO-S inhibition normalizes cardiac output and increases blood pressure, it aggravates vasoconstriction in the SI and does not improve hypoperfusion.
 ...
PMID:Nitric oxide synthase inhibition aggravates intestinal microvascular vasoconstriction and hypoperfusion of bacteremia. 751 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>